1. Field of the Invention
The present invention relates to a method for treating a neurological disorder using a slow-release vehicle for delivery of a therapeutic agent to the cerebrospinal fluid (CSF) of a human.
2. Description of the Related Art
Neurological disorders are among the most difficult diseases to treat. A major complicating factor in treating such disorders is the inability of many drugs to penetrate the blood-brain barrier when the agent is administered systemically. This ineffectiveness of classical drug delivery to address this need is particularly problematic with respect to chronic neurological disorders, such as those caused by benign or malignant cell proliferation or various viral etiologic agents.
Among the most difficult chronic neurological disorders to treat are those derived from metastatic infiltration, such as neoplastic meningitis. Neoplastic meningitis results from the metastatic infiltration of the leptomeninges by cancer, and is most commonly a complication of acute leukemia, lymphoma, or carcinoma of the breast and lung. Autopsy studies indicate that 5 to 8 percent of solid tumor patients develop metastasis to the leptomeninges during the course of disease. Evidence suggests that the incidence of neoplastic meningitis may be increasing, in part due to increased survival from effective systemic therapies. (Bleyer, Curr. Probl. Cancer, 12:184, 1988).
Standard treatment for neoplastic meningitis includes single agent or combination intrathecal chemotherapy and radiation therapy. Radiotherapy to the entire neuraxis often produces severe marrow depression and has not been satisfactory in controlling active leptomeningeal disease except in leukemic meningitis. (Kogan, in Principle and Practice of Radiation Oncology, Perez, et al. eds., Lippincott, Philadelphia, Pa., pp. 1280-1281, 1987). Systemic chemotherapy likewise is not generally effective in active meningeal malignancy because of poor drug penetration through the blood-brain barrier. (Biasberg, et al., Can. Treat. Rep., 61:633, 1977; Shapiro, et eL, New Eng. J. Med., 293:161, 1975). Cytarabine, one of the three chemotherapeutic agents most commonly used for intrathecal therapy of neoplastic meningitis, is a cell-cycle phase specific agent that kills cells only when DNA is being synthesized. Consequently, optimal tumor kill with agents such as cytarabine requires constant infusion or frequent daily injections to maintain therapeutic concentrations for extended periods in CSF. This procedure is uncomfortable for patients, time consuming for physicians, and associated with an increased risk of infectious meningitis. Therefore, there is a need for a slow-releasing depot formulation which can allow a therapeutic agent to persist in contact with a neurological disorder in order to achieve an ameliorative effect. The present invention addresses this need.